Early versus delayed erythropoietin for the anaemia of end-stage kidney disease

  • Protocol
  • Intervention

Authors

  • Jorge Coronado Daza,

    Corresponding author
    1. Universidad de Cartagena, Facultad de Medicina, Departamento Médico, Grupo de Investigación Alta Tensión, Cartagena, Bolivar, Colombia
    • Jorge Coronado Daza, Facultad de Medicina, Departamento Médico, Grupo de Investigación Alta Tensión, Universidad de Cartagena, Sede Zaragocilla, Campus de la Salud, Cartagena, Bolivar, 130015, Colombia. jocodada@yahoo.es.

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  • Amaury Ariza García,

    1. Universidad de Cartagena, Facultad de Medicina, Departamento Médico, Grupo de Investigación Alta Tensión, Cartagena, Bolivar, Colombia
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  • Joaquín Rodelo Ceballos,

    1. University of Antioquia, Hospital Universitario San Vicente Fundacion, Servicio de Nefrologia, Medellin, Antioquia, Colombia
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  • Nancy Yomayusa González,

    1. Universidad Sanitas, Bogotá, Clínica Colsanitas. Grupo de Investigación Traslacional, Bogota, Cundinamarca, Colombia
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  • Gerard Urrútia,

    1. CIBER Epidemiología y Salud Pública (CIBERESP), Spain, Iberoamerican Cochrane Centre - IIB Sant Pau, Barcelona, Spain
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  • César Loza Munárriz,

    1. Universidad Peruana Cayetano Heredia, Departamento de Nefrología, Lima, Peru
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  • Carol Páez-Canro

    1. Universidad Nacional de Colombia, Instituto de Investigaciones Clínicas, Facultad de Medicina, Bogota, Colombia
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Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the clinical benefits and harms of early versus delayed EPO for anaemia in patients with ESKD undergoing haemodialysis or peritoneal dialysis.

Background

Description of the condition

Anaemia has been defined by the World Health Organization (WHO) as a haemoglobin concentration less than 13.0 g/dL and 12.0 g/dL respectively for males and non-pregnant females aged 15 years or over (WHO 2008). This definition is widely accepted for people with anaemia caused by chronic kidney disease (CKD) (KDIGO 2012).

Anaemia is a common complication in people with CKD and develops early in the course of the disease. Anaemia increases in frequency with a corresponding decline in kidney function, and peaks in incidence at the end-stage kidney disease (ESKD) (Astor 2002). Renal anaemia develops mainly as a consequence of relative erythropoietin (EPO) deficiency in relation to haemoglobin levels; EPO levels are 10 to 100 times higher among anaemic patients with normal kidney function (Artunc 2007; Ly 2004; McGonigle 1984).

Description of the intervention

EPO is an essential growth factor for the recruitment, differentiation, maintenance and survival of erythroid progenitor cells. EPO is produced by hepatocytes in the foetal stage, and after birth is synthesised mainly by the kidneys in response to hypoxia (Glaspy 2009; Jelkmann 2011). After cloning the EPO gene in 1983, recombinant human technology enabled development and production of the first erythropoietin - epoetin-α - which was approved for clinical use in 1989 (Eschbach 1988; Eschbach 1989). Since then, many types of EPOs - also called erythropoiesis-stimulating agents (ESAs) - have been produced. According to their action time, they are classified as short-acting and long-acting (Hörl 2013).

Short-acting ESAs have a half-life from six to eight hours intravenously and from 19 to 24 hours subcutaneously; most are administered two to three times weekly (Halstenson 1991). Short-acting ESAs are more effective when administered subcutaneously. Alfa and beta are the most widely used short-acting ESAs. Epoetin-α biosimilars are being used in Europe (Schellekens 2008).

Long-acting ESAs have improved pharmacokinetic and pharmacodynamic characteristics. Dose requirements do not differ according to the route of administration. The combination of a significantly increased half-life and lower binding affinity for the EPO receptor explains why long-acting ESAs stimulate erythropoiesis for longer periods. Long-acting ESAs used for the treatment of renal anaemia are darbepoetin-α and the continuous EPO receptor activator (CERA). One darbepoetin dose is given every one or two weeks (Macdougall 1999; Padhi 2006) and CERA is administered biweekly or monthly (Macdougall 2006).

EPO therapy improves cognitive functions and the quality of life for the patient (Astor 2002; Drueke 2006; Pfeffer 2009; Ross 2002). It helps the regression of left ventricular hypertrophy (Levin 2002; Parfrey 2009), but it is not free of complications which are mainly hypertensive reactions, thrombosis of arteriovenous fistula in patients on haemodialysis, increased risk of stroke and faster tumour growth; appearance of severe anaemia as part of pure red cell aplasia and seizures (Del Vecchio 2010; Rizzo 2010; Zhu 2006).

How the intervention might work

Erythropoietin acts as an essential growth factor. It regulates erythropoiesis, maintaining the survival of erythroid progenitors, stimulating their proliferation and differentiation in the bone marrow (Jelkmann 2011). The EPO production is markedly up-regulated by hypoxia by a negative feedback loop; the hypoxia induces an increase in EPO hormone production in the kidney, increasing the mass of circulating red blood cells, thereby increasing the oxygen- carrying capacity of blood and suppressing further expression of EPO (Bunn 2013). Specifically, EPO binds to the EPO receptor through the high affinity isoform EPO, which is responsible for the erythropoietic effects by activation of several pathways (hypoxia-inducible factor 1, 2 and 3, Janus kinase-2, phosphatidylinositol 3-kinase, protein kinase C, anti-apoptotic protein) stimulating the differentiation of erythroid precursor cells and inhibiting the apoptosis of erythroid progenitors (Elliott 2008; Sinclair 2013).

Recombinant human EPO and human EPO have similar biological activity. The increase in red blood cell mass is dependent on the exposure time of the level of EPO; therefore, subcutaneous administration of short-acting ESAs is more effective (Kaufman 1998). The response to the administration of EPO may vary from patient to patient. The dose should be adjusted to reach a haemoglobin monthly increase between 1 and 2 g/dL. If the increase is less than expected, the dose is increased by 25%; if higher, it is decreased by 25%. After reaching the target haemoglobin level, the maintenance dose of EPO is adjusted according to the monthly haemoglobin readings. (KDOQI 2006; Del Vecchio 2010; KDIGO 2012).

Why it is important to do this review

The importance of this systematic review is based on the following premises.

  1. Many of the clinical manifestations of CKD may be epiphenomenon of anaemia, which is associated with the worsening of cognitive functions, exercise capacity, mental acuity, quality of life; depression and fatigue (Finkelstein 2009; Gerson 2004; Weisbord 2008); in addition, an increased risk of cardiovascular morbidity and mortality may be present (Astor 2006; Glassock 2009; Locatelli 2004).

  2. ESAs have changed the history of the treatment of anaemia in CKD by improving the signs and symptoms of severe anaemia, avoiding the complications of iron overload, transmission of viral diseases and sensitisation for future kidney transplants (Del Vecchio 2010). However, no benefits have been found in randomised controlled trials (RCTs) and meta-analysis when correcting anaemia with regards to patients’ mortality and noncardiac fatal events, except for quality of life. Notwithstanding, a relationship between the use of ESAs and an increased cardiovascular morbidity and mortality in patients with CKD was found in the studies comparing full anaemia correction versus partial anaemia correction (Pfeffer 2009; Phrommintikul 2007; Singh 2006); patients with cancer also present an increased cardiovascular morbidity and mortality with the use of ESAs (Pfeffer 2009; Rizzo 2010; Tonia 2012).

  3. From 2000 to 2009 the different clinical guidelines in the United States and Europe recommended to start treatment with ESAs when haemoglobin was less than 11 g/dL (EBPG 2004; ERBP 2009; ERBP 2010; K/DOQI 2000; KDOQI 2006; KDOQI 2007; KDIGO 2008). Not until 2012 did the Work Group of Kidney Disease Improving Global Outcomes (KDIGO) guidelines suggest starting treatment in dialysis patients when haemoglobin is between 9 to 10 g/dL (Grade 2B), and in some cases, starting it when haemoglobin is greater than 10 g/dL (not graded), primarily in the elderly where life expectancy is lower, being more relevant to improve the quality of life (KDIGO 2012). The European Renal Best Practice (ERBP) Advisory Board and Canadian Society of Nephrology agree with the KDIGO group about the decision of whether and when to start ESA therapy in dialysis patients (ERBP 2013; Moist 2013).

There are several systematic reviews in the literature about treatment with ESAs for anaemia in patients with CKD and ESKD that evaluate the level of haemoglobin, energy and physical function, fatigue, left ventricular mass index and mortality (Johansen 2010; Johansen 2012; Palmer 2010; Parfrey 2009; Vinhas 2012), but to the date, a systematic review on the benefits and harms of early (haemoglobin less than 11 g/dL but greater than 10 g/dL) versus delayed (haemoglobin ≤ 10 g/dL) treatment with ESAs for anaemia in dialysis patients with ESKD has not yet been published.

Objectives

To assess the clinical benefits and harms of early versus delayed EPO for anaemia in patients with ESKD undergoing haemodialysis or peritoneal dialysis.

Methods

Criteria for considering studies for this review

Types of studies

This review will include all the RCTs and quasi-RCTs (RCTs in which allocation to treatment was obtained by alternation, the use of alternate medical records, date of birth or other predictable methods) looking at EPO in people with ESKD on dialysis with anaemia. Studies will be considered without language restriction. Studies of at least 12 weeks follow-up will be included.

Types of participants

Inclusion criteria

Dialysis patients with anaemia due to ESKD irrespective of gender or age. We will accept any definition of anaemia provided in each individual study.

Exclusion criteria

We will exclude studies involving patients with functional or absolute iron deficiency.

Types of interventions

This review will include studies of early (haemoglobin between 10 and 11 g/dL) versus delayed (haemoglobin ≤ 10 g/dL) treatment with any EPO or EPO against placebo/no treatment, by any route (subcutaneous or intravenous) or dose. The following comparisons will be considered for inclusion.

  • EPO versus placebo/no treatment

  • EPO versus EPO

Types of outcome measures

We will evaluate all-cause mortality and cardiovascular mortality according to the report at the end of each study. In addition, according to the length of the follow-up, we will assess the outcomes on mortality at the short (< 6 months), medium (from 6 to 12 months) and long term (> 12 months). We will evaluate the number of adverse and cardiovascular events according to their appearance during study follow-up.

Primary outcomes
  1. All-cause mortality

  2. Cardiovascular mortality

  3. Quality of life (end of treatment scores obtained using validated tools such as the Kidney Disease Quality of Life tool or others as mentioned in the studies).

Secondary outcomes
  1. Adverse events: hypertension (one or more hypertensive events requiring additional antihypertensive medication or as defined by the investigators); seizure ≥ 1 event)

  2. Myocardial infarction (fatal or non-fatal)

  3. Stroke (ischaemic or haemorrhagic, either fatal or non-fatal)

  4. Thrombotic events (deep venous thrombosis, peripheral arterial thrombotic events, and dialysis vascular access thrombosis)

  5. Blood transfusions requirements (number of individuals requiring one or more packed red blood cell transfusion)

  6. Haemoglobin level reached at end of study.

Search methods for identification of studies

Electronic searches

We will search the Cochrane Renal Group's Specialised Register through contact with the Trials' Search Co-ordinator using search terms relevant to this review. The Cochrane Renal Group’s Specialised Register contains studies identified from several sources.

  1. Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)

  2. Weekly searches of MEDLINE OVID SP

  3. Handsearching of renal-related journals and the proceedings of major renal conferences

  4. Searching of the current year of EMBASE OVID SP

  5. Weekly current awareness alerts for selected renal journals

  6. Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Studies contained in the Specialised Register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of the Cochrane Renal Group. Details of these strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available in the Specialised Register section of information about the Cochrane Renal Group.

See Appendix 1 for search terms used in the strategies for this review.

Searching other resources

  1. Reference lists of review articles, relevant studies and clinical practice guidelines.

  2. Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.

Data collection and analysis

Selection of studies

The search strategy will be used to obtain titles and abstracts of studies that may be relevant to the review. Titles and abstracts will be screened independently by two authors, who will discard studies that do not meet all the selection criteria. Reasons for exclusions at this stage of assessment will be recorded. We will obtain full-text copies of studies that are potentially relevant for closer examination. This will also be undertaken for studies whose titles and abstracts do not provide enough information to make a decision. The two authors will independently assess the complete text of these citations to determine which report studies satisfy the inclusion criteria. Disagreements during the study identification and data extraction process will be resolved in consultation with a third author who will also provide methodological assistance.

Data extraction and management

Two authors will carry out data extraction independently using standard data extraction forms. Studies not reported in English or Spanish will be translated before assessment. Where more than one publication of one study exists, we will group the reports together and will use the publication with the most complete data in the analyses. Where relevant outcomes are only published in earlier versions, we will use these data. Any discrepancy between published versions will be highlighted. We will resolve disagreements by consultation with a third author.

Assessment of risk of bias in included studies

The following items will be independently assessed by two authors using the risk of bias assessment tool (Higgins 2011) (see Appendix 2).

  • Was there adequate sequence generation (selection bias)?

  • Was allocation adequately concealed (selection bias)?

  • Was knowledge of the allocated interventions adequately prevented during the study (detection bias)?

    • Participants and personnel

    • Outcome assessors

  • Were incomplete outcome data adequately addressed (attrition bias)?

  • Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?

  • Was the study apparently free of other problems that could put it at a risk of bias?

Measures of treatment effect

We will express results as risk ratios (RR) or risk difference (RD) together with 95% confidence intervals (CI) for dichotomous outcomes (all-cause mortality, cardiovascular mortality, overall myocardial infarction, overall stroke, vascular access thrombosis, adverse effects of treatment, transfusion). We will calculate RR and 95% CI within individual studies from the number of events and numbers of participants at risk extracted from each included study.

We will calculate the mean difference (MD) and CI 95% for haemoglobin for continuous data. We plan to calculate the standardised mean difference (SMD) with CI 95% for quality of life where different scales may be used.

Unit of analysis issues

We will use the individual patient as the unit of analysis in parallel studies.

Dealing with missing data

We will request any further information required from the original author in written (e.g. email or a letter to the corresponding author) and any relevant information obtained in this manner will be included in the review. Evaluation of important numerical data such as screened, randomised patients as well as intention-to-treat, as-treated and per-protocol population will be carefully performed. We will record attrition rates, (e.g. drop-outs, losses to follow-up and withdrawals). Issues of missing data and imputation methods (e.g. last observation carried forward) will be critically appraised (Higgins 2011).

Assessment of heterogeneity

We will analyse heterogeneity using a Chi² test with N-1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I² test (Higgins 2003). This will be explored by pre-specified subgroup analysis. We will consider substantial statistical heterogeneity if I² is greater than 50% (Higgins 2011).

Assessment of reporting biases

We will use funnel plot of the primary outcome to provide a visual assessment of whether treatment estimates are associated with study size. We will attempt to assess whether the review is subjected to publication bias by using a funnel plot to illustrate variability graphically between studies. If at least 10 studies are available it will be possible to make judgments about asymmetry, and if asymmetry is present, causes other than publication bias will be explored (Sterne 2011). We will use two tests to assess funnel plot asymmetry: the adjusted rank correlation test (Begg 1994) and the regression asymmetry test (Egger 1997).

Data synthesis

We will pool data using the random-effects model and we will also use the fixed-effect model to ensure the robustness of the model chosen and the susceptibility to outliers.

Subgroup analysis and investigation of heterogeneity

We will use subgroup analysis to explore possible sources of heterogeneity (e.g. participants, interventions and study quality). Heterogeneity among participants could be related to age and modalities of dialysis used. Heterogeneity in treatments could be related to dose, type (short acting versus long acting) and duration of ESAs treatment. Quality of life parameters will be assessed based on the Kidney Disease Quality of Life tool, or others as mentioned in the studies (Hays 1997). We will research the following factors in subgroup analyses.

  • Patients on haemodialysis versus peritoneal dialysis

  • Paediatric versus adult participants

  • Use of EPO higher doses versus lower dose

  • EPO short-acting versus long-acting

  • Use the Kidney Disease Quality of Life tool versus others as mentioned in the studies.

We will analyse subgroups by timing of measurement of outcome provided there is a wide range of intervention periods in the included studies and it appears this could be a source of heterogeneity.

Subgroup analysis will only be conducted on primary outcomes.

Sensitivity analysis

We will perform sensitivity analysis in order to explore the influence of the following factors on the effect on size.

  • Repeating the analysis excluding unpublished studies

  • Repeating the analysis taking into account risk of bias

  • Repeating the analysis excluding any very long or large studies to establish how much they dominate the results

  • Repeating the analysis excluding quasi-RCTs.

Summary of findings tables

We will use the principles of the GRADE system (Guyatt 2008) to assess the quality of the body of evidence associated with all main outcomes (all-cause mortality, cardiovascular mortality, quality of life, cardiovascular events, adverse events, haemoglobin level reached at the end of the study, and blood transfusions requirements) and we will construct a Summary of Findings (SoF) table using the GRADE profiler software (GRADEpro 2008). The GRADE approach appraises the quality of a body of evidence based on the extent of confidence that an estimate of effect or association actually reflects the item being assessed. The valuation of the quality of a body of evidence considers within the risk of bias assessment (methodological quality), the directness of the evidence, heterogeneity in the data, precision of effect estimates and risk of publication bias (Balshem 2011; Guyatt 2011; Guyatt 2013).

Acknowledgements

We acknowledge the assistance of the Cochrane Renal Group editorial office and the Iberoamerican Cochrane Centre during the development of this protocol. We would also like to thank the referees for their kind feedback and advice during the preparation of this protocol.

Appendices

Appendix 1. Electronic search strategies

DatabaseSearch terms
CENTRAL
  1. "renal replacement therapy":ti,ab,kw

  2. h*emodialysis:ti,ab,kw

  3. h*emodiafiltration:ti,ab,kw

  4. dialysis:ti,ab,kw

  5. (CAPD or CCPD or APD):ti,ab,kw

  6. ("endstage kidney" or "endstage renal" or "end-stage kidney" or "end-stage renal"):ti,ab,kw

  7. (ESKD or ESKF or ESRD or ESRF):ti,ab,kw

  8. ("chronic kidney" or "chronic renal"):ti,ab,kw

  9. {or #1-#8}

  10. an*emi*:ti,ab,kw

  11. {and #9-#10}

  12. erythropoie*:ti,ab,kw

  13. epo?etin:ti,ab,kw

  14. darbepoetin:ti,ab,kw

  15. EPO:ti,ab,kw

  16. rhEPO:ti,ab,kw

  17. CERA:ti,ab,kw

  18. Mircera:ti,ab,kw

  19. (Epogen or Eprex or Procrit or Epoyet):ti,ab,kw

  20. (Binacrit or Retacrit or Eporatio):ti,ab,kw

  21. Aranesp:ti,ab,kw

  22. {or #12-#21}

  23. {and #11, #22}

  24. (early or delay* or defer* or late):ti,ab,kw

  25. {and #11, #24}

  26. {or #23, #25}

MEDLINE
  1. exp Renal Dialysis/

  2. exp Hemofiltration/

  3. Kidney Failure, Chronic/

  4. dialysis.tw.

  5. (hemodialysis or haemodialysis).tw.

  6. (hemodiafiltration or haemodiafiltration).tw.

  7. (CAPD or CCPD or APD).tw.

  8. (end-stage kidney or end-stage renal or endstage kidney or endstage renal).tw.

  9. (ESKD or ESKF or ESRD or ESRF).tw.

  10. or/1-9

  11. Anemia/

  12. exp Anemia, Hypochromic/

  13. an?emi*.tw.

  14. or/11-13

  15. and/10,14

  16. exp Erythropoietin/

  17. erythropoie*.tw.

  18. epo?etin.tw.

  19. darbepoetin.tw.

  20. EPO.tw.

  21. rhEPO.tw.

  22. CERA.tw.

  23. Mircera.tw.

  24. (Epogen or Eprex or Procrit or Epoyet).tw.

  25. (Binacrit or Retacrit or Eporatio).tw.

  26. Aranesp.tw.

  27. or/16-26

  28. and/15,27

  29. (early or delay* or defer* or late).tw.

  30. and/15,29

  31. or/28,30

EMBASE
  1. exp Renal Replacement Therapy/

  2. (hemodialysis or haemodialysis).tw.

  3. (hemodiafiltration or haemodiafiltration).tw.

  4. dialysis.tw.

  5. (CAPD or CCPD or APD).tw.

  6. Chronic Kidney Disease/

  7. Kidney Failure/

  8. Chronic Kidney Failure/

  9. (end-stage renal or end-stage kidney or endstage renal or endstage kidney).tw.

  10. (ESRF or ESKF or ESRD or ESKD).tw.

  11. or/1-10

  12. Anemia/

  13. Iron deficiency anemia/

  14. an?emi*.tw.

  15. or/12-14

  16. and/11,15

  17. erythropoietin/

  18. recombinant erythropoietin/

  19. novel erythropoiesis stimulating protein/

  20. erythropoie*.tw.

  21. epo?etin.tw.

  22. darbepoetin.tw.

  23. EPO.tw.

  24. rhEPO.tw.

  25. CERA.tw.

  26. Mircera.tw.

  27. (Epogen or Eprex or Procrit or Epoyet).tw.

  28. (Binacrit or Retacrit or Eporatio).tw.

  29. Aranesp.tw.

  30. or/17-29

  31. and/16,30

  32. Early intervention/

  33. (early or delay* or defer* or late).tw.

  34. or/32-33

  35. and/16,34

  36. or/31,35

Appendix 2. Risk of bias assessment tool

Potential source of bias Assessment criteria

Random sequence generation

Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence

Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random).
High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
Unclear: Insufficient information about the sequence generation process to permit judgement.

Allocation concealment

Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment

Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web-based, and pharmacy-controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non-opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
Unclear: Randomisation stated but no information on method used is available.

Blinding of participants and personnel

Performance bias due to knowledge of the allocated interventions by participants and personnel during the study

Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
Unclear: Insufficient information to permit judgement

Blinding of outcome assessment

Detection bias due to knowledge of the allocated interventions by outcome assessors.

Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
Unclear: Insufficient information to permit judgement

Incomplete outcome data

Attrition bias due to amount, nature or handling of incomplete outcome data.

Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as-treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.
Unclear: Insufficient information to permit judgement

Selective reporting

Reporting bias due to selective outcome reporting

Low risk of bias: The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon).
High risk of bias: Not all of the study’s pre-specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified; one or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
Unclear: Insufficient information to permit judgement

Other bias

Bias due to problems not covered elsewhere in the table

Low risk of bias: The study appears to be free of other sources of bias.
High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data-dependent process (including a formal-stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.

Appendix 3. Glossary

Epoetin Biosimilars: a biological medicinal product referring to an existing one and submitted to regulatory authorities for marketing authorization by an independent applicant after the existing agents' protection expires. Biosimilars can resemble the agents on which they are modelled but cannot fully copy their properties (Hörl 2013; Schellekens 2008).

Erythropoiesis-stimulating agents: an agent similar to the cytokine (erythropoietin) that stimulates red blood cell production, commonly abbreviated ESAs (Hörl 2013).

Erythropoietin high dose: subcutaneous doses > 120 UI/kg/wk, or intravenous doses > 240 UI/kg/wk of epoetin alfa or beta or biosimilars; darbepoetin alfa corrected weekly ESAs doses can be calculated multiplying by 200; and the continuous erythropoietin receptor activator can be calculated as per the pharmacological equivalence (Kainz 2010; Tolman 2005).

European Best Practice Guidelines (EBPG): The first EBPG for the Management of Anaemia in Patients with Chronic Renal Failure were created to fulfil the need for recommendations that reflected current European clinical practice and experience. They were presented at the ERA-EDTA Congress in Madrid in 1999. They were prompted from the need to analyse the huge volume of published data on anaemia management (Zoccali 2008).

European Renal Best Practice (ERBP): The ERA-EDTA in 2008 opted to change the name EBPG to European Renal Best Practice (ERBP) as a means of acknowledging that, especially in nephrology, it is difficult to generate real ‘guidelines’ because of the lack of sufficient evidence (Zoccali 2008).

KDIGO: Kidney Disease Improving Global Outcomes (KDIGO) was established in 2003 as an independently incorporated non-profit foundation governed by an international Board. The Mission is to improve the care and outcomes of kidney disease patients worldwide through the development and implementation of global clinical practice guidelines. KDIGO is led by an international Board comprised of approximately 50 members. The majority of the Board members are practicing nephrologists, but it also includes patient representatives, professionals from other medical specialties and disciplines – nephrology nurses, dieticians and social workers (KDIGO 2003).

KDOQI: In 1995, the National Kidney Foundation (NKF) began the development of what would become the first broadly accepted clinical practice guidelines in nephrology, now known as KDOQI—Kidney Disease Outcomes Quality Initiative. The first guidelines were published in 1997, and today there are 13 guidelines, which have made a major difference in the quality of care for kidney patients in the United States and worldwide (KDOQI 2014).

Long-acting erythropoiesis-stimulating agent: an agent with a half-life from 24 to 134 hours when given intravenously and from 54 to 134 hours when given subcutaneously. It is administered once every two to four weeks to maintain haemoglobin levels (Hörl 2013).

Short-acting erythropoiesis-stimulating agent: an agent with a half-life from six to eight hours when given intravenously and from 19 to 24 hours when given subcutaneously. It is administered twice or three times weekly to maintain haemoglobin levels (Hörl 2013).

Contributions of authors

  1. Draft the protocol: JC, JR, NY, GU, AA, CL, CP

  2. Study selection: JC, AA

  3. Extract data from studies: JC, AA

  4. Enter data into RevMan: JC, GU, CL

  5. Carry out the analysis: JC, AA, JR, CL, NY, CP

  6. Interpret the analysis: JC, AA, JR, CL, NY, CP

  7. Draft the final review: JC, GU, CL

  8. Disagreement resolution: JR

  9. Update the review: JC, AA

Declarations of interest

Jorge Coronado, Amaury Ariza, Joaquin Rodelo, Nancy Yomayusa, Gerard Urrutia, Cesar Loza and Carol Paéz: none known.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Cartagena, University, Colombia.

    Full time professor salary

Ancillary